—_——
`
`(1 1) Document No. AU-B-22042/88
`(12) PATENT ABRIDGMENT
`
`(19) AUSTRALIAN PATENT OFFICE (1 0) Acceptance No. 626798
`(54)
`Title
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`International Patent C|assification(s)
`(51)“ A-s1Ko31/40
`A61K031/13
`A61 K 031/405
`(51)~" A61K 047/10
`
`A61K 047/18
`
`(21) Application No. : 22042138
`(30)
`Priority Data
`
`A61Ko31/19
`
`A61K 031/195
`
`(22) Application Date I 09-09-88
`
`(31) Number
`096173
`
`(32) Date
`11.09.87
`
`(33) Country
`Us UNITED STATES OF AMERlCA
`
`(43)
`
`(44)
`
`Publication Date 1 16.03.89
`
`Publication Date of Accepted Application : 13.08.92
`
`(71) Applicant(s)
`SYNT~EX (U.S.A.) INC.
`
`(72)
`
`lnventor(s)
`CHERNG-CHYI ROGER FU; DEBORAH M. LIDGATE
`
`(74) Attorney or Agent
`WATERMARK PATENT & TRADEMARK ATTORNEYS , Locked Bag 5, HAWTHORN‘ VIC 3122
`
`(57)
`
`Claim
`
`An ophthalmic NSAID formulation comprising:
`1.
`a NSAID 1n an effective amount for ophthalmic treatment,
`
`a stabilizing amount
`3 Quaternary ammonium preservative,
`of a nonionic ethoxylated octylphenol surfactant, and an
`aqueous vehicle.
`
`An antimicrobially effective ophthalmologicaily acceptable preservative system
`22.
`for ophthalmologically acceptable, carboxyl group-‘containing drugs, said preservative
`system comprising a quaternary ammonium preservative and a stabilizing amount of a
`nonionic ethoxylaled octylphenol surfactant.
`
`(’
`
`x=~«*1x9fl:.u..4;..~ x;Ar-'~—
`
`
`
`wlnnopharma EX10T Pacjefi1“w*
`!&&’($#)%# -0$#$$" /143 $
`
`

`
`COMMONWEALTH OF AUSTRALIA
`
`PATENTS ACT 1952-69
`
`Form 10
`
`C3C3|\/IPLETE SPECIFICATION
`
`.Wm626798
`
`Class
`
`Int. Class
`
`Application Number:
`Lodged:
`
`Complete Specification Lodged:
`Accepted:
`
`.
`. .
`‘o 'o§riority :.
`
`Published:
`
`. ‘- ' ' ‘iielated An :
`
`.:.::Name of APn“ca-1“
`
`SYNTEX (U . is . A.)
`
`INC.
`
`3401 Hillview Avenue , Palo Alto , California 94304 , Ufni ted
`.
`. "
`”"Address of Applicant: States of America
`»
`
`mm, ,mm:
`
`CHERN’G—CHY I ROGER FU and DEBORAH M. LIDGAT E1,
`
`Address for Service:
`
`EDWD' WATERS & SONS’
`59 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
`
`Complete Speeifieation for the invention entitled:
`
`PRESERVATIVE SYSTEM‘ FOR OPHTHALMIC FORM‘ULATIONS
`
`.
`The foliowing statement is a full description of this invention, including the best method of performing it im@§‘srn~%§> 7-.
`
`US
`
`_
`
`'
`
`«K-3-It-JEN!-+_
`
`Innopharma EX1011, Page 2
`!&&’($#)%# -0$#$$" /143 %
`
`

`
`5
`
`-19
`
`.
`..
`"":
`n3?’
`f:::-
`
`§‘.}
`3-_;
`°
`°°
`
`.:.:.
`_-;§_
`"'
`
`.":'.
`.‘
`.
`
`.::?=
`
`10
`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`BACKGROUND OF THE INVENTION
`The present invention relates to improved ophthalmic
`formulations, particularly to ophthalmic formulations for
`anti-inflammatory drugs, and specifically to an improved
`
`preservative system for ophthalmic formulations of
`carboxyl
`("—COOH") group-containing drugs, especially
`non—steroidal anti-inflammatory drugs ("NSAIDS").
`
`The invention also relates to methods of using these
`formulations for treating diseases that are either caused
`by, associated with or accompanied by inflammatory
`processes,
`including, among others, glaucoma, cystoid
`
`15
`
`20
`
`macular edema, uveitis, diabetic retinopathy, and
`conjunctivitis, or any trauma caused by eye surgery or
`eye injury.
`
`25
`
`The topical use of NSAIDS, particularly pyrrolo
`pyrroles,
`in the treatment of ophthalmic diseases was
`
`first taught
`
`in UVS. Patent No. 4,454,151, where NSAID
`
`compounds (such as those described in U.S. Patents
`
`30
`
`4,089,969; 4,232,038; 4,087,539 and 4,097y579) were
`
`exemplified in formulation with NaH2POa'H2O,
`Na2HPD4°H20, Naci, benzalkonium chloride ("BAG")
`and sterilized water. while the formulations described
`
`I
`
`35
`
`8408Y
`
`gyghlanI-
`
`26280-FF
`
`!&&’($#)%# -0$#$$" /143 &
`Innopharma EX1011, Page 3
`
`

`
`-2-
`
`in the '15l patent were efficacious, an insoluble complex
`was found to form between the NSAID and the BAC.
`The
`
`formulations became cloudy or turbid and did not,
`
`therefore, have the stability desired for shelf life in
`
`5
`
`commercial applications. A reasonable minimum shelf life
`
`(that is,
`
`the time during which a solution remains clear
`
`and retains its pharmaceutical activity) is at least
`
`about one year, representing sufficient time to package,
`
`ship, and store a formulation without having to replace
`
`1o
`
`expired stock too frequently.
`
`The solutions of the
`
`present invention have shown a shelf life of at least one
`
`invention entails an improvement
`the present
`year. Thus,
`over the formulations described in the 'l5l patent.
`
`In general, an ophthalmic formulation contains an
`15 active compound and various ophthalmologically acceptable
`excipients,
`in the form of a solution, an ointment,
`a
`suspension, etc.
`An excipient is ophthalmologically
`acceptable if it is non—irritating to the eye and if its
`
`active ingredient penetrates the blood-aqueous barrier
`
`20 and/or diffuses through the various ocular substructures
`to the site where it is pharmacologically active.
`The
`excipients can include a tonicifier,
`a preservative,
`a
`
`surfactant, a buffering system, a chelating agent, a
`viscosity agent as well as other stabilizing agents.
`
`25 Ophthalmic formulations must be sterile, and if intended
`
`for multiple dosing regimens, must be preserved with an
`effective anti-microbial agent.
`
`Drgano-mercurials (e.g.,
`
`thimerosal, phenylmercuric
`
`acetate and phenylmercuric nitrate) have been used
`
`30 extensively as the preservative in ophthalmic solutions.
`
`These compounds, however, pose difficulties due to
`
`potential mercury toxicity as well as poor chemical
`
`stability. Benzalkonium chloride,
`
`a quaternary ammonium
`
`compound, has been widely used in ophthalmic solutions,
`35 and is considered to be the preservative of choice.
`
`8408Y
`
`26280-FF
`
`‘y'.E
`
`..3..
`_3°"_
`x...
`.::'E
`'-'-3
`
`.o.m.
`:::
`'3--°
`
`.m:|.
`
`¢"..
`
`V
`
`K
`
`!&&’($#)%# -0$#$$" /143 ’
`Innopharma EX1011, Page 4
`‘..__..._..ol:
`
`

`
`F
`
`[
`
`-3-
`
`However, BAC has typically been considered to be
`
`incompatible with anionic drugs (e.g., salicylates or
`
`nitrates, etc.),
`
`forming insoluble complexes which cause
`
`the solution to become cloudy or turbid.
`
`Such a complex
`
`5
`
`between the anionic drug and benzalkonium chloride can
`
`cause a decrease in the pharmaceutical activity of
`
`the
`
`anionic drug.
`
`Many NSAIDS (such as ketorolac,
`
`indomethacin,
`
`flurbiprofen and diclofenac) are being developed for
`
`10 ocular use because of their activity as anti-inflammatory
`
`agents including their ability to prevent cystoid macular
`edema.
`
`In the past, as in the case with other ophthalmic
`
`15
`
`drugs that contain a -COUH group, antiinflammatory
`solutions of NSAIDS for occular use have proven to be
`incompatible with quaternary ammonium compounds such as
`BAC. This incompatibility is due to the fact that
`the
`—CO0H group can form a complex with the quaternary
`
`ammonium compounds, rendering the preservative less
`
`20 available to serve its function, and reducing the
`activity of the active ingredient.
`Indomethacin
`ophthalmic formulations have been prepared, however,
`these are suspensions, not solutions. Ucufen Ophthalmic
`solution, an NSAID (flurbiprofen) approved by the FDA for
`
`25 ophthalmic use,
`
`incorporates thimerosal (with EDTA) as
`
`In U.S. patent 4,454,151 there
`its preservative system;
`is a disclosure of an ophthalmic formulation using
`
`ketorolac, benzalkonium chloride (as the preservative)
`
`and polysorbate 80, however the solution became cloudy or
`
`30 turbid after a short period of time.
`
`It has remained desired to provide a stable, clear,
`antimicrobially effective ophthalmic formulation with a
`
`prolonged shelf life for
`
`-CUOH group containing
`
`ophthalmic drugs, especially NSAIDS, using BAC as the
`35 preservative.
`
`3408Y
`
`26280—FF
`
`-23.3
`
`:5"
`Fan‘
`3".
`.::'E
`°-'-3
`
`...
`.:.:.
`°-°n'
`s_:a
`" '
`
`.H:.
`
`E 2 3 3 3
`
`
`
`!&&’($#)%# -0$#$$" /143 (
`Innopharma EX1011, Page 5
`_ _.:__._rr__;_i __-.,l
`
`

`
`-4-
`
`SUMMARY OF THE INVENTION
`
`It has now been discovered that stable, clear and
`
`antimicrobially effective, NSAID-containing ophthalmic
`
`formulations can be prepared which include a quaternary
`
`5
`
`ammonium preservative. These solutions have an improved
`
`shelf life, exhibiting no cloudiness or turbidity over
`
`extended periods.
`
`In one aspect of the invention,
`
`these compositions
`
`include an ophthalmologically effective amount of a
`
`10 NSAID,
`
`a quaternary ammonium preservative and a
`
`stabilizing amount of an ethoxylated octylphenol as a
`
`nonionic surfactant, all in an aqueous vehicle.
`Another aspect is an ophthalmic composition
`
`including an ophthalmologically effective amount of a
`15 NSAID, a quaternary ammonium preservate and a stabilizing
`amount of an ethoxylated octylphenol as a nonionic
`surfactant.
`Another aspect is an ophthalmic composition
`
`including an ophthalmologically effective amount of a
`
`20 NSAID, benzalkonium chloride as a preservative and a
`stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant.
`
`Another aspect is an ophthalmic composition
`including an ophthalmologically effective amount of a
`
`25 NSAID, benzalkonium chloride as a preservative and a
`
`stabilizing amount of Octoxynol 40 as a nonionic
`surfactant.
`
`Another aspect is an ophthalmic composition
`
`including an ophthalmologically effective amount of
`
`30 ketorolac or an isomer, an ester, or a pharmaceutically
`acceptable salt thereof, benzalkonium chloride as a
`
`preservative and a stabilizing amount of Uctoxynol 40 as
`a nonionic surfactant.
`
`°:a.§
`
`":i"
`,°"-,
`;::}.
`:_':
`'-'-3
`
`...
`.:.:.
`3'93
`
`"..‘
`n'.:
`
`‘Hz.’
`
`8408Y
`
`26280-FF
`
`.386527 -0$#$$" /143 )
`Metrics EX1011, Page 6
`
`

`
`-5-
`
`In another aspect of the invention, methods for
`
`treating ophthalmic diseases in mammals using the
`
`ophthalmic pharmaceutical formulations of the invention
`are also disclosed. These diseases are those that are
`
`5
`
`either caused by, associated with or accompanied by
`
`inflammatory processes,
`
`including, among others,
`
`glaucoma, cystoid macular edema, uveitis, diabetic
`
`retinopathy and conjunctivitis, or any trauma caused by
`
`eye surgery or eye injury.
`
`10
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`Definitions
`D
`
`As used herein,
`
`the term "NSAID" means an
`
`ophthalmologically acceptable non-steroidal
`
`15
`
`anti-inflammatory drug.
`
`The NSAID's include, for
`
`example, flurbiprofen, ketorolac, diclofenac,
`
`indomethacin, and the isomers, esters, and
`
`pharmaceutically acceptable salts thereof.
`
`As used herein,
`the term "q.s." means adding a
`20 quantity sufficient to achieve a stated function, e.g.,
`
`to bring a solution to the desired volume (i.e., 100%).
`
`As used herein,
`
`the term "treatment" or "treating"
`
`including:
`means any treatment of a disease in a mammal,
`(i) preventing the disease,
`that is, causing the
`
`35
`
`clinical symptoms of
`
`the disease not
`
`to develop;
`
`(ii)
`
`inhibiting the disease,
`
`that is, arresting the
`
`development of clinical symptoms; and/or
`
`(iii)
`
`relieving the disease,
`
`that is, causing the
`
`regression of clinical symptoms;
`
`30
`
`the term "effective amount" means a
`As used herein,
`dosage sufficient to provide treatment for the disease
`
`state being treated. This will vary depending on the
`
`patient,
`
`the disease and the treatment being effected.
`
`8408Y
`
`26280-FF
`
`!&&’($#)%# -0$#$$" /143 *
`Innopharma EX1011, Page 7
`
`:
`
`“
`
`
`
`z
`
`

`
`
`
`0
`
`ti
`.
`
`I
`
`I
`
`n
`
`C
`
`0
`0
`on
`I!!!
`0
`onto
`IIII
`9000
`at
`n
`to
`1
`
`D
`
`I
`
`C
`
`p
`g
`It
`0
`U
`no
`
`-5-
`
`As used herein,
`
`the term "antimicrobially effective"
`
`means ability to withstand the U.S. Pharmacopia
`
`antimicrobial challenge.
`
`As used herein,
`
`the term "surfactant" means a
`
`nonionic surfactant, preferably ethoxylated octylphenol
`
`compounds as described below.
`
`As used herein,
`
`the term "quaternary ammonium
`
`preservative" means a quaternary ammonium compound such
`as described below.
`
`As used herein,
`
`the term "stabilizing" means keeping
`
`a formulation clear and antimicrobially effective for its
`
`minimum reasonable shelf life, e.g., at least one year.
`
`Formulations
`
`The formulations of the present
`
`invention include an
`
`NSAID active agent
`
`in an effective amount for ophthalmic
`
`treatment, a quaternary ammonium preservative,
`
`a
`
`stabilizing amount of an ethoxylated octylphenol as a
`
`nonionic surfactant, optionally including other
`
`excipients such as a chelating agent,
`
`a tonicifier,
`
`a
`
`buffering system,
`
`a viscosity agent as well as other
`
`10
`
`15
`
`20
`
`stabilizing agents. Ophthalmic solutions and suspensions
`
`typically contain an aqueous vehicle rather than an oily
`
`vehicle. Ophthalmic formulations must be sterile, and if
`
`25
`
`intended for multiple dosing regimens, must be
`
`antimicrobially effective for their minimum reasonable
`
`shelf life, e.g., at least one year, and preferably two
`
`to three years or more.
`
`The ingredients used in the
`
`formulations of
`
`the present invention are typically
`
`30
`
`commercially available or can be made by methods readily
`known to those skilled in the art.
`
`Pharmaceutical ophthalmic formulations typically
`
`,contain an effective amount, e.g., 0.001% to 10% wt/vol.,
`
`preferably 0.002% to 5% wt/vol, most preferably 0.005% to
`
`35
`
`1% wt/vol of an active ingredient (e.g.,
`
`the NSAID or the
`
`8408Y
`
`26280-FF
`
`0
`
`0 II
`u
`0 at
`0 as
`9 u_
`0 no
`
`I
`
`1
`
`0
`
`0090
`0
`on
`
`O
`0
`
`
`
`!&&’($#)%# -0$#$$" /143 +
`Innopharma EX1011, Page 8
`
`
`

`
`
`
`-7-
`
`present invention)-
`
`The amount of active ingredient will
`
`vary with the particular formulation and the disease
`
`state for which it is intended.
`
`The total Concentration
`
`of solutes should be such that,
`
`if possible,
`
`the
`
`resulting solution is isotonic with the lacrimal fluid
`
`(though this is not absolutely necessary) and has a pH in
`
`the range of 6 to 8.
`
`The formulations of the present
`
`invention are
`
`prepared as solutions incorporating the above—described
`
`ingredients within the following approximate ranges:
`
`Ingredient
`
`Active Agent
`
`Preservative
`
`Surfactant
`
`Amount
`
`0.001% to 10.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`Other Excipients
`
`0% to 10.0% wt/vo1.; and
`
`Purified Water
`
`q.s.
`
`to 100%.
`
`Uptional other excipients, such as a chelating agent and
`
`a tonicifier, are used in the following approximate
`
`proportions:
`
`Ingredient
`Chelating agent
`
`Amount
`0.01% to l.0%wt/vol.;
`
`Tonicifier
`
`q.s.
`
`to achieve
`
`1N Na0H or 1N HCl
`
`isotonicity with
`
`lacrimal fluid; and
`
`to adjust pH to
`q.s.
`6.0 to 8.0.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`8408Y
`
`26280-FF
`
`
`
`!&&’($#)%# -0$#$$" /143 ,
`Innopharma EX1011, Page 9
`
`

`
`-3-
`
`In a preferred ophthalmic NSAID solution,
`
`the
`
`ingredients are combined in the following proportions:
`
`Ingredient
`
`Amount
`
`NSAID
`
`BAO
`
`0.002% to 5.0% wt/vol.;
`
`0.002% to 1.0% wt/vol.;
`
`(50% aq. soln.)
`
`Octoxynol 40
`
`0.001% to 1.0% wt/vol.;
`
`(70% aq. soln.)
`
`EDTA Naz
`Nacl
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with
`
`lacrimal fluid;
`
`1N NaOH or 1N HC1 q.s.
`
`to adjust pH to
`
`Purified water
`
`q.s.
`
`to 100%.
`
`7.4t0.4; and
`
`the
`In another preferred ophthalmic NSAID solution,
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`
`NSAID
`
`0.005% to 1.0% wt/vol.;
`
`BAC
`(50% aq. soln.)
`Uctoxynol 40
`
`(70% aq. soln.)
`EDTA Naz
`Nacl
`
`0.002% to 1.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with
`
`lacrimal fluid;
`1N NaOH or 1N H01 q.s.
`to adjust pH to
`
`Purified water
`
`q.s.
`
`to 100%.
`
`17.4¢0.4; and
`
`5
`
`10
`
`.5
`
`20
`.
`
`25
`
`30
`
`-.-,3
`
`';‘°
`;:::._
`:?°_
`'°.°:
`'23.;
`
`,,,
`.:3:‘
`‘-3-’
`
`..1..
`" '
`
`n..
`”"‘
`
`‘
`
`I
`
`9
`
`8408Y
`
`26280—FF
`
`!&&’($#)%# -0$#$$" /143 $#
`Innopharma EX1011, Page 10
`
`
`
`
`
`
`—-9»-we-ss:ir3avI<")IaA».r--—-
`
`

`
`
`
`9
`
`In a more preferred ophthalmic NSAID solution, the ingredients are combined in
`
`the following proportions:
`
`IIlflL£Ld.i.e.I1i
`
`NSAlD
`
`BAG
`
`Ameum
`
`0.50% wt/vol.;
`
`0.02% wt/vo|.;
`
`(50% aq. soln.)
`
`Octoxynol 40
`
`0.01% wt/vol.;
`
`(70% aq. soln.)
`
`EDTANa2
`
`NaCl
`
`0.10% wt/vol.;
`
`q.s. for isotonicity with lacrimal
`
`fluid;
`
`1N NaOH or 1N HCI
`
`q.s. to adjust pH to 7.4 i 0.4; and
`
`Purified Water
`
`q.s. to 100%.
`
`5
`
`10
`
`15
`
`The invention relates primarily to formulations having as the active agent
`
`ophthalmologically acceptable drugs [including the isomers (as either the (d)- or (1).-
`
`isomer) esters and pharmaceutically acceptable salts thereof) that can form a complex
`
`with a quaternary ammonium compound, particularly NSAlDs and drugs with a carboxyl
`
`group.
`
`20
`
`NSA|Ds useful
`
`in the practice of this invention include, for example, ketorolac
`
`(and the other compounds described as being ophthalmologically effective in U.S. Patent
`
`No. 4,454,151 to Waterbury,
`
`issued June 12, 1984,
`
`the pertinent portions of which
`
`f
`
`are incorporated herein by reference),
`
`indomethacin,
`
`flurbiprofen sodium, and
`
`diclofenac, including the isomers, esters and pharmaceut.ica|ly acceptable salts thereof.
`Preservatives, useful
`in the formulations of
`the present
`invention include
`
`25
`
`quaternary ammonium compounds,
`
`such as cetyltrimethylammonium bromide,
`
`cetylpytridinium chloride and ben-zalkonium chloride, preferably, benzalkonium chloride.
`
`
`
`4'
`
`Innopharma EX1011, Page 11
`!&&’($#)%# -0$#$$" /143 $$
`
`
`
`
`
`
`«Mural113).‘-'-12A,’--~.
`
`

`
`-10-
`
`The nonionic surfactants useful
`
`in the formulations
`
`of the present invention are preferably ethoxylated
`
`octylphenol compounds, such as octylphenoxypoly-
`
`(ethyleneoxy)ethanols, more preferably,
`
`a homologous
`
`5
`
`series of surfactants sold under the trade name Igepal CA
`
`with a numerical suffix indicating the mole ratio of
`
`ethylene oxide to octylphenol,
`
`the ratio being 3 to 40.
`
`Examples include Uctoxynol 9, Octoxynol l2, Ootoxynol 13,
`
`and Octoxynol 40, and most preferably Octoxynol 40,
`
`10 manufactured and sold by GAF under the trade name Igepal
`
`CA897 (a 70% aqueous solution of Octoxynol 40).
`
`Among the optional excipients,
`the chelating agents
`useful in the formulations of the present invention
`include 8-hydroxyquinoline sulfate, citric acid, and
`15 preferably disodium edetate. Under certain conditions,
`the chelating agent may also enhance the anti—microbial
`effect due to its ability to render essential metal ions
`unavailable to the microbes.
`
`Buffering systems optionally useful
`
`in the
`
`20
`
`formulations of the present invention are based on, for
`example, citrate, borate, or phosphate.
`Tonicifiers optionally useful in the formulations of
`
`the present invention include dextrose, potassium
`chloride and/or sodium chloride, preferably sodium
`
`,
`‘
`
`25 chloride.
`
`tviscosity agents optionally useful in the
`formulations of the present invention include the
`
`cellulose derivatives such as hydroxypropylmethyl
`
`cellulose,
`
`sodium carboxymethylcellulose, and
`
`30 hydroxyethylcellulose.
`
`Other optional excipients useful in the formulations
`
`of the present invention include stabilizing agents such
`
`as antioxidants, e.g.,
`
`sodium metabisulfate and ascorbic
`
`acid, depending on the NSAID used.
`
`35
`
`8408Y
`
`2628.0-FF
`
`fi'5§
`fi"
`t::,
`.:?‘:
`'-'-3
`':x.E
`
`,,,
`"2’.
`’§::‘
`
`u_,
`3":
`
`"._
`" '
`
`1
`
`'
`
`Innopharma EX1011, Page 12
`!&&’($#)%# -0$#$$" /143 $%
`
`

`
`These formulations are prepared by dissolving the
`
`solutes (e.g.,
`
`the NSAID,
`
`the preservative,
`
`the
`
`surfactant,
`
`the chelating agent, and the buffering agent)
`
`in a suitable quantity of water, adjusting the pH to
`
`about 6 to 8, preferably 6.8 to 8.0 and most preferably
`
`7.4, making a final volume adjustment
`
`to 100% with
`
`additional water, and sterilizing the preparation using
`
`any suitable method known to those in the art.
`
`It has been discovered that ophthalmic formulations
`
`incorporating the preservative system of
`
`the invention are
`
`physically stable (i.e., remain clear) and functionally
`
`stable (i.e., remain antimicrobially effective) for at
`
`least the minimum reasonable shelf life of such products.
`
`Preferred Formulations
`
`The preferred preservative system of
`
`the invention
`
`includes a quaternary ammonium preservative and a
`
`stabilizing amount of a nonionic surfactant.
`
`The preferred ophthalmic formulation of the
`
`invention includes a NSAID active agent
`
`in an effective
`
`amount for ophthalmic treatment and an antimicrobially
`
`effective amount of
`
`the above-described preferred
`
`preservative system.
`
`The preferred preservative of the invention is
`
`benzalkonium chloride.
`
`The preferred surfactant of the invention is
`
`Octoxynol 40, especially when combined with benzalkonium
`
`chloride as the preservative.
`
`The preferred chelating agent of the invention is
`
`disodium edetate, especially when combined with
`
`benzalkonium chloride as the preservative and
`
`Octoxynol 40 as the nonionic surfactant.
`
`5
`
`10
`
`«5
`
`20’
`
`25
`
`30
`
`The preferred ophthalmic solutions of the invention
`
`include a NSAID, benzalkonium chloride, Octoxynol 40 and
`disodium edetate.
`
`35
`
`8408Y
`
`2628e~F‘f“
`
`T75
`
`!&&’($#)%# -0$#$$" /143 $&
`Innopharma EX1011, Page 13
`
`

`
`-12-
`
`A preferred ophthalmic NSAID solution,
`
`the
`
`ingredients are combined in the following proportions:
`
`Ingredient
`
`Amount
`
`NSAIO
`BAD
`
`0.002% to 5.0% wt/vo1.;
`0.002% to 1.0% wt/vo1.;
`
`(50% aq. soln.)
`
`Octoxynol 40
`
`0.001% to 1.0% wt/vol.;
`
`(70% ad. soln.)
`
`EDTA Naz
`NaCl
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity
`
`with lacrimal fluid;
`
`1N NaOH or 1N H01
`
`q.s.
`
`to adjust pH to
`
`Purified Water
`
`7.4:0.£L; and
`q.s.
`to 100%.
`
`the
`Another preferred ophthalmic NSAIO solution,
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`NSAID
`o.oo5% to 1.0% wt/vol.;
`
`BAG
`(50% ad. soln.)
`octoxynol as
`
`(70% aq. soln.)
`EDTA N32
`Nacl
`
`1N Na0H or 1N HCI
`
`0.002% to 1.0% wt/vo1.;
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity
`
`with lacrimal fluid;
`q.s.
`to adjust pH to
`
`7.4:0.4; and
`
`Purified Water
`
`q.s.
`
`to 100%.
`
`."..§
`.g--
`‘III.
`.'""
`i-'3
`-T-j
`
`_
`':’:o'
`-Z-2';
`
`..u
`
`'...
`‘-3 3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`8408Y
`
`26280-FF
`
`!&&’($#)%# -0$#$$" /143 $’
`Innopharma EX1011, Page 14
`
`

`
`-13-
`
`A preferred ophthalmic NSAID solution has the
`
`following formulation:
`
`Ingredient
`NSAID
`
`BAC
`
`Amount
`
`0.50% wt/vol,
`
`0.02% wt/vol.
`
`(50% aq. soln.)
`
`Octoxynol 40
`
`0.01% wt/vol.
`
`(70% ad. soln.)
`
`EDTA Na2
`NaCl
`
`0.10% wt/vol.
`
`q.s. for isotonicity
`with lacrimal fluid
`
`lN NaOH or lN HCl
`
`q.s.
`
`to adjust pH to
`
`Purified water
`
`q.s.
`
`to 100%
`
`7.4i0.4
`
`5
`
`10
`
`15
`
`Most preferred is the ophthalmic solution according
`
`to the above formulation wherein the NSAID is Ketorolac
`
`Tromethamine or an isomer thereof.
`
`
`20 Utility and Administration
`
`This invention is directed to NSAID ophthalmic
`
`formulations and a method useful for treating ophthalmic
`diseases in mammals.
`These diseases are either caused
`
`by, associated with or accompanied by inflammatory
`
`25 processes,
`
`including, among others, glaucoma, cystoid
`
`macular edema, uveitis, diabetic retinopathy and
`
`conjunctivitis, or any trauma caused by eye surgery or
`
`eye injury.
`
`The method of this invention is both curative and
`
`30 preventative. Where applied, for example, pre-surgically
`
`or immediately post-traumatically, i.e. before
`
`inflammation develops, it prevents development of
`
`inflammation. when applied directly to-the eye suffering
`
`from any of the named ophthalmic diseases, it supresses
`
`35 already developed inflammatory processes.
`
`8&O8Y
`
`26280-FF
`
`
`
`
`
`
`*E)((101Z1—,—Page;1§fi
`
`lnnop
`hanna
`!&&’($#)%# -0$#$$" /143 $(
`
`

`
`-.14-
`
`Ophthalmic formulations are typically administered
`
`by topical application to the eyelids or for instillation
`
`into the space (cul-de-sac) between the eyeball and the
`
`eyelids, of topically applied ophthalmic solutions,
`
`5
`
`suspensions or ointments, or by subconjunctival injection.
`
`The dosage level will, of course, depend on the
`
`concentration of the drops,
`
`the condition of the subject
`
`and the individual magnitude of responses to treatment.
`
`However,
`
`typical dosage ranges might be about 2 to 10
`
`10
`
`drops of 0.5% solution of active ingredient per day.
`
`For a more detailed discussion of ophthalmic
`
`formulations, their pteparation and administration, see
`
`-
`
`-
`
`-
`
`Remington's Pharmaceutical Sciences, 15th Ed., pages
`
`1489-1504,
`
`(1975).
`
`15
`
`Testing
`
`Ophthalmic formulations such as the solutions of the
`
`present invention are typically tested for physical
`
`stability, chemical stability, and preservative efficacy,
`
`20 both when they ire first manufactured and after a fixed
`
`period of time (e.g., after two years).
`
`They are
`
`generally considered to be safe and clinically acceptable
`
`if proven to be well tolerated in the eye.
`
`Physical stability is determined by observation of a
`
`25
`
`solution after expiration of a fixed period of time.
`
`A
`
`solution is considered to be physically stable if its
`
`appearance (e.g., color and clarity) does not change and
`
`if the pH remains constant, within acceptable limits.
`
`Chemical stability involves a routine chemical analysis
`
`30 of the solution,
`
`to be sure that its active ingredient
`
`and the excipients have not changed after a fixed period
`of time.
`
`Preservative efficacy is tested by.the procedure
`
`described in the U.S. Pharmacopia Compendiary, whereby a’
`
`8‘*°8Y
`
`26280-FF
`
`!&&’($#)%# -0$#$$" /143 $)
`Innopharma EX1011, Page 16
`
`
`

`
`-15-
`
`solution is challenged with a microbe and a determination
`
`is made as to whether the microbe survives in it.
`
`EXAMPLES
`
`The following examples are given to enable those
`
`skilled in the art to more clearly understand and to
`
`practice the present invention.
`
`They should not be
`
`considered as a limitation on the scope of the invention,
`
`10
`
`but merely as being illustrative and representative
`
`thereof.
`
`-23.5
`
`:::;3
`::".
`.:_2E
`‘-'-3
`
`3_..
`;j:'
`‘-3-’
`
`...5
`.""
`
`‘,q,.
`”‘
`‘
`
`15
`
`20
`
`25
`
`EXAMPLE 1
`
`This example illustrates the preparation of a
`representative pharmaceutical formulation for ophthalmic
`administration containing the NSAID Ketorolac
`Tromethamine.
`
`ingredient
`Ketorolac Tromethamine
`_BAC
`
`Amount
`o.50% wt/vol.
`0.02% wt/vol.
`
`(50% sq. soln.)
`Octoxynol 40
`
`(70% aq. soln.)
`
`EDTA N32
`Nacl
`
`0.01% wt/vol.
`
`0.10% wt/vol.
`0.79% wt/vol.
`
`The above ingredients are mixed, adding purified
`
`the pH is adjusted to
`30 water until they are dissolved,
`7.4fiD.A and the balance of the formulation is made up
`
`with purified water, adding a quantity sufficient to make
`
`100% volume.
`
`The solution is then sterilized.
`
`Other NSAIDS or their isomers, salts or esters,
`
`such
`
`35 as those described above, can be used as the active
`
`8fi08Y
`
`26280-FF
`
`!&&’($#)%# -0$#$$" /143 $*
`Innopharma EX1011, Page 17
`
`

`
`3°x§
`‘-3-
`'x:,
`'jf“:
`'-'-3
`-23,3
`
`...
`‘3--'
`§’:§'
`
`n‘.
`3-‘3
`
`_‘..
`'--'3
`
`-15-
`
`compound in the preparation of the formulation of this
`
`example.
`
`EXAMPLE 2
`
`This example illustrates the preparation of a
`
`representative pharmaceutical formulation for ophthalmic
`
`administration containing the NSAID Ketorolae
`
`Tromethamine.
`
`Ingredient
`
`Amount
`
`Ketorolae Tromethamine
`
`0.50% wt/vol.
`
`BRC
`(50% ad. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Naz
`Nacl
`
`0.02% wt/vol.
`
`0.02% wt/vol.
`
`0.20% wt/vole
`o.79% wt/vol.
`
`5
`
`10
`
`15
`
`20
`
`The above ingredients are mixed, adding purified
`water until they are dissolved,
`the pH is adjusted to
`7»4i0.4 and the balance of the formulation is made up
`
`with purified water, adding a quantity sufficient to make
`100% volume.
`The solution is then sterilizede
`
`fi
`
`25
`
`Other NSAIDs or their isomers, salts or esters, such
`
`as those described above, can be used as the active
`compound in the preparation of the formulation of this
`
`example.
`
`39
`
`EXAMPLE 3
`
`This example illustrates the preparation of
`
`a
`
`representative pharmaceutical formulation for ophthalmic
`
`5408Y
`
`26280-FF
`
`
`
`!&&’($#)%# -0$#$$" /143 $+
`Innopharma EX1011, Page 18 5
`
`

`
`-17-
`
`administration containing the NSAID Ketorolac
`
`Tromethamine.
`
`Ingredient
`
`Amount
`
`Ketorolac Tromethamine
`
`0.10% wt/vol.
`
`BAG
`
`0.004% wt/vol.
`
`(50% aq. soln.)
`
`Octoxynol 40
`
`0.004% wt/vol.
`
`(70% aq. soln.)
`
`..-_:
`.
`
`‘out.
`._
`
`10
`
`EDTA Naz
`Nacl
`
`0.05% wt/vol.
`0.88% wt/vol.
`
`The above ingredients are mixed, adding purified
`
`the pH is adjusted to
`water until they are dissolved,
`7.4i0.4 and the balance of the formulation is made up
`
`15 with purified water, adding a quantity sufficient to make
`100% volume.
`The solution is then sterilized.
`Other NSAIDs their isomers, salts or esters, such as
`
`those described above, can be used as the active compound
`
`in the preparation of the formulation of this example.
`
`20
`
`EXAMPLE 4
`
`",_
`
`This example illustrates the preparation of a
`
`representative pharmaceutical formulation for ophthalmic
`
`25 administration containing the NSAID flurbiprofen sodium.
`
`ingredient
`Flurbiprofen Sodium
`BAC
`
`Amount
`a}03% wt/vol.
`0.@2% wt/vol.
`
`30
`
`(50% ad. soln.)
`
`Uctoxynol 40
`
`0.01% wt/vol.
`
`(70% aq. soln.)
`
`EDTA Na2
`Nacl
`
`0.10% wt/vol.
`0.90% wt/vol.
`
`35
`
`The above ingredients are mixed, adding purified
`
`8408Y
`
`26280-FF
`
`9
`
`/V~.—.—.—~
`
`‘
`
`!&&’($#)%# -0$#$$" /143 $,
`Innopharma EX1011, Page 19
`
`

`
`y
`
`"
`
`4
`
`.
`
`.
`
`-13-
`
`water until they are dissolved,
`
`the pH is adjusted to
`
`7.4i0.4 and the balance of
`
`the formulation is made up
`
`with purified water, adding a quantity sufficient to make
`100% volume.
`The solution is then sterilized.
`
`5
`
`Other ophthalmic drugs and NSAIDs, such as those
`
`described above, can be used as the active compound in
`
`the preparation of the formulation of this example.
`
`10
`
`EXAMPLE 5
`
`Physical stability of the formulations of the
`
`present
`
`invention is measured by preparing clear
`
`in the concentrations shown in the table
`formulations,
`below, sealing them in sterilized containers, and
`15 observing the clarity of the solution after a period of
`one month and again after five months, Solutions that
`remain clear are considered stable in this procedure.
`The formulations of the present invention have
`proven to be stable when tested in accordance with the
`
`20 above procedure. Formulations using surfactants other
`than the nonionic surfactants of the invention did not
`remain clear and were not stable.
`
`Three surfactants were evaluated for their ability
`to dissolve the ketorolac — benzalkonium chloride complex
`
`25 and maintain a physically clear solution over an extended
`
`period of time. The three surfactants tested were:
`Octoxynol 40; Polysorbate 80 (Tween 80); and Myrj 52.
`
`Two concentrations of each surfactant were incorporated
`
`into the ophthalmic formulation, and these were placed at
`
`30 various temperatures for future visual observations.
`
`.:3_§
`goo
`.:::._
`.::":
`°~°-3
`{'°j
`
`__..
`3°-3
`§‘:?
`
`"._
`3-'3
`
`“_.
`'--'3
`
`I
`
`35
`
`8408Y
`
`26280~FF
`
`Innopharma EX1011, Page 20
`!&&’($#)%# -0$#$$" /143 %#
`
`
`

`
`1
`
`*
`
`i
`
`-
`
`u
`
`v
`
`‘
`
`.
`
`g
`3
`
`-j%_§
`2"
`:II:._
`:::'
`9
`':
`
`2
`
`_,_
`3’§"
`':i:’
`
`._‘r.
`
`”,.
`"'
`
`'
`
`-19-
`
`Octoxynol 40
`0.004% 0.02%
`
`Tween 80
`0.0035% 0.01%
`
`Myrj 52
`0.00l5% 0.01%
`
`1 month
`
`5
`
`60°C
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`40°C
`
`clear
`
`clear
`
`very
`very
`turbid turbid
`
`turbid
`
`turbid
`
`RT
`
`clear clear
`
`turbid turbid clear
`
`4-40°C
`
`clear
`
`clear
`
`turbid turbid clear
`
`clear
`
`clear
`
`10
`
`15
`
`5 month
`
`60°C
`
`clear clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`aooc
`RT
`
`clear
`clear
`
`clear
`clear
`
`turbid turbid turbid
`turbid turbid turbid
`
`turbid
`turbid
`
`At the 5 month time period it was apparent that
`the Octoxynol 40 surfactant was superior to the other two
`
`surfactants. At 5 months, Tween 80 and Myrj 52 displayed
`
`turbidity when stored at RT.
`
`The presence of turbidity
`
`20
`
`suggested the inability to solubilize a precipitate
`formation between the Ketorolac moiety and benzalkonium
`chloride.
`
`A further study has shown a 2 year shelf life
`for the ophthalmic formulation; Precipitate formation
`
`25 and turbidity are not a problem with this formulation.
`
`Preservative efficacy is maintained throughout the 2 year
`shelf life.
`
`30
`
`EXAMPLE 6
`
`Preservative efficacy of
`
`the formulations of the
`
`present invention is measured by preparing formulations,
`
`e.g., according to the foregoing Examples, and subjecting
`
`35 them to the U.S. Pharmaeopia antimicrobial challenge.
`
`8408Y
`
`26280-FF
`
`*
`
`3
`
`(
`
`.1-
`
`!&&’($#)%# -0$#$$" /143 %$
`Innopharma EX1011, Page 21
`
`
`

`
`-20-
`
`The formulations of the present invention
`
`demonstrate preservative efficacy when tested in
`
`accordance with the above procedure.
`
`5
`
`EXAMPLE 7
`
`The objective of this clinical efficacy study was to
`
`compare the effectiveness and safety of ketorolac with a
`
`control solution in reducing inflammation following
`
`10
`
`cataract removal and intraocular lens implantation. All
`
`patients underwent an extracapsular cataract extraction
`
`with intraocular lens implantation 1 day following
`initiation of treatment.
`
`Ophthalmic examinations were performed
`
`15 preoperatively (within 3 weeks of surgery) and during the
`
`first week (postoperative days 1 to 3), second Week
`
`(postoperative days A through 12), and third week
`
`(postoperative days 15 through 27) of treatment.
`
`Particular attention was given to signs and symptoms
`
`20 consistent with inflammation. Among the ocular
`
`characteristics assessed on a scale of none, mild,
`
`moderate, or severe were:
`
`lid edema, corneal edema,
`
`conjunctival injections, ciliary flush, and the presence
`of cells and flare in the anterior chamber.
`
`25
`
`Fluarophotometry: Anterior segment
`
`inflammation
`
`(i.e., iritis, cyclitis, iridocyclitis) is by definition
`
`a disruption of the blood-aqueous barrier. when
`
`inflammation is present, a care